The central purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in cardiac anesthesiology. The applicant proposes to acquire additional skills in molecular biology and somatic gene transfer in the context of a project that builds upon his previous experience in studying myocardial ischemia-reperfusion injury in vivo. Myocardial ischemia-reperfusion injury has been identified in many clinically important conditions including acute myocardial infarction and cardiac surgery. The goal of the selected project is to understand the mechanisms underlying the beneficial effects of nitric oxide (NO) donors in cardiac ischemia reperfusion injury (IR). The applicant has previously demonstrated that endogenous NO release reduces myocardial infarction in vivo. However, systemic NO-donors have complex effects that potentially modulate many elements important in the development of IR. These include circulating blood elements (leukocytes, platelets, and erythrocytes), the vasculature, and the heart itself. The applicants hypothesize that the beneficial effects of NO-donors in IR derive primarily from their effect on circulating blood elements. To test this hypothesis, they will 1) examine the direct effects of NO on cardiocyte survival in an in vitro model of ischemia-reperfusion, 2) evaluate the effects of inhaled NO gas (which exclusively affects the pulmonary circulation and the circulating blood elements) in a rat model of cardiac IR, and 3) examine the effects of local cardiac overexpression of NO synthase (NOS) in the same rat model, to affect the heart primarily and, to a lesser extent, the circulating blood elements as they traffic through the heart. In this way, they hope to define the relative importance of NO modulation of local (cardiac) versus systemic (circulating blood elements) pathways in the attenuation of IR. Understanding the role of these pathways in cardiac IR and developing approaches to modulation of these pathways, may provide novel therapeutic approaches for the management of important clinical conditions such as myocardial infarction and cardiac surgery.